The most aggressive and life threatening forms of cancer frequently develop a resistance to chemotherapy because of high expression of survival genes in these tissues. For example, pancreatic cancer has a very low survival rate and a very high rate of chemotherapy resistance. Moreover, many current chemotherapy treatments are extremely toxic to the patient since they are not targeted to a particular tumor tissue. Taken together, there is a large need to develop alternative and specialized cancer treatments to reduce side effects and tumor resistance to chemotherapy treatments.
RNA interference (RNAi) enables sequence specific gene silencing by promoting degradation of specific mRNAs with short double-stranded RNA molecules (siRNA). Administering naked RNA molecules is not a practical therapeutic strategy because of instability of the siRNA in circulating blood. Unprotected siRNAs are degraded by ribonucleases in serum soon after intravenous delivery.
Formulating siRNA within polymeric or lipid nanoparticles (LNPs) is a strategy to prevent degradation. Stable nucleic acid lipid particle (SNALP) typically contain an ionizable lipid, a neutral helper lipid, cholesterol, and a diffusible polyethylene glycol (PEG)-lipid. See Semple et al., Nature Biotech, 2010, 28(2), 172-6. In another example, transferrin receptor targeted cyclodextrin polymer nanoparticles carrying siRNAs have been reported. See Zuckerman et al., J Invest Dermatol, 2011, 131, 453-60.
Medarova et al. report in vivo imaging of siRNA delivery and silencing in tumors using magnetic iron oxide nanoparticles (IONPs) conjugated with siRNAs. Nat Med, 2007, 13, 372-377.
Chen et al. report nanoparticles modified with tumor-targeting scFv deliver siRNA and microRNA for cancer therapy. See Mol Ther, 2010, 18(9):1650-6.
Sliva and Schnierle report selective gene silencing by viral delivery of short hairpin RNA. See Virology J, 2010, 7:248
Particles and RNA interference are reported in a number of patent references. See, e.g., U.S. Pat. No. 8,313,772, U.S. Pat. No. 8,258,288, U.S. Pat. No. 8,222,220, US201202250, US20120225125, US201002849, US20100284921, US2010048623, US20040204377, US20050008617, EP1818417, EP 2136788, EP 2257280, EP 2295045, EP 2207903, WO2009114476, WO20080153771, WO2004029213, WO2008073856, WO2012167028, WO2007118065.
References cited herein are not an admission of prior art.